tbuckley/cabot-search huggingface dataset:
First in class TLR7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiation therapy in patients with advanced pancreatic adenocarcinoma: Results from the AGADIR study.
Authors: Simon Pernot, Paul Sargos, Philippe Rochigneux, François Ghiringhelli, Lola Jade Palmieri, Sophie Cousin, Jean Philippe Guégan, Jean David Fumet, Vincent Bourbonne, Alban Bessede, Jean Philippe Metges, Antoine Italiano
Journal: Journal of Clinical Oncology (2023)

4153 Background: Pancreatic adenocarcinoma is refractory to immune checkpoint inhibitors such as PD1/PDL1 antagonists. Investigating alternative immunotherapeutic approaches is a crucial need for this devastating disease. The potent immunostimulatory effects of Toll-like receptor (TLRs) have spurred efforts aimed at the development of TLR agonists as new immune-oncology agents. Radiation therapy combined with TLRs agonists has been shown to enhance antitumor immunity in the preclinical setting. Methods: AGADIR is a multi-cohort, phase 2, multicenter, open-label study investigating the novel TLR 7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced cancers. Cohort A enrolled patients with advanced pancreatic adenocarcinoma. BDB001 was administered IV at the dose of 0.75 mg/m² on days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 on day 1 every 3 weeks. Atezolizumab was given at the dose of 1200 mg every 3 weeks. SBRT of at least one metastatic lesion was started at least one week after the first administration of atezolizumab and at the latest before the Cycle 2 Day 1. The primary endpoint is disease control rate defined as the proportion of participants with complete response, partial response or stable disease, as per adapted RECIST v1.1, observed within 24 weeks of treatment onset. Secondary endpoints include objective response, progression-free survival, overall survival and safety. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 32 pts were enrolled in 3 centers (14 male, 18 female). Median age was 64 years (range 38 – 78). Median number of previous treatment lines was 1 (range 1 – 5). The most common treatment related adverse events were grade 1/2 asthenia, chills and fever. No death was related to the treatment. Among the 21 patients for whom central review was performed at the time of this writing, best tumor response was confirmed partial response, stable disease and progressive disease in 2 (9.5%), 6 (28.5%) and 13 (62.0%) patients respectively. The disease control rate was 38.0% (95%CI 18.1-61.5). Conclusions: The AGADIR study met its first endpoint for disease control rate in patients with advanced pancreatic cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03915678 .
The mutational landscape of circulating cell free DNA in patients with gastric cancer.
Authors: Yan Qian, Shirong Cai, Dandan Zhu, Junfeng Zhou, Jia Guo, Shuhua Zhao, Shifu Chen, Shihou Sheng
Journal: Journal of Clinical Oncology (2023)

e16055 Background: Gastric cancer (GC) is a malignant tumor with a high lethality rate, with the highest incidence occurring in China. Gastric cancer is phenotypically heterogeneous, therefore the identification of genomic alteration is crucial for guiding clinical treatment. In this study, we aimed to use liquid biopsies to detect somatic mutations of GC patients and describe the mutational landscape of circulating tumor DNA. Methods: The blood samples of 157 Chinese patients with gastric malignancies were collected between 2018 to 2022. Somatic alterations were detected by either whole exome sequencing or high-depth targeted gene panel sequencing of ctDNA, using white blood cells as germline DNA control. Results: In our cohort, 1002 alterations of 323 genes were detected from plasma samples. We used MutSigCV tool to define the significantly mutated genes (SMG) and identified 16 SMG. Overall, the five most common mutated genes were TP53 (52.6%), LRP1B (15.4%), ARID1A(14.7%), SYNE1(12.2%), CDH1(10.9%). Recurrent mutations were identified in TP53 genes including c.524G &gt; A, c.713G &gt; T, which lead to loss of function of P53 protein according to evidence of clinical actionability from OncoKB (http://oncokb.org/). Genetic amplification of ERBB2 was detected in 8 patients (5.1%). 6 out of 95 samples were microsatellite instability (MSI), 3 were MSI-H and 3 were MSI-L.The median blood tumor mutation burden (bTMB) of all samples was 1.97 (range 0–143.51) mutations/Mb, 2 patients (1.27%) to high bTMB (≥ 20 mutations/Mb), 37 patients (23.57%) to intermediate bTMB (5-19 mutations/Mb), 118 patients (75.16%) to low bTMB ( &lt; 5 mutations/Mb). The Co-occurrence and mutual exclusivity of gastric cancer variations was investigated. Mutually exclusive mutation patterns were observed in TP53-KRAS (p &lt; 0.05), TP53-ARID1A (p &lt; 0.05), TP53-CDH1 (p &lt; 0.05) gene pairs. In addition, Gene Ontology (GO) and KEGG analysis were performed to analyze enrichment of somatic mutated genes and understand their biological function. The altered signaling pathway included PI3K−Akt signaling, MAPK signaling, Ras signaling, Rap1 signaling etc. 61 genes with somatic mutations were enriched to PI3K–Akt signaling pathway. Conclusions: In this study, we characterized the somatic mutational landscape of gastric cancer in 157 Chinese patients utilizing ctDNA which might guide clinical treatment.
A novel approach to the treatment of high-risk non–muscle-invasive bladder cancer: Combining immune checkpoint inhibitor (ICI) and microtubule inhibitor (MTI).
Authors: Hailong Hu, Yuanjie Niu, Hong Zheng Li, Chong Shen, Shiwang Huang, Yunkai Qie, Zhouliang Wu, Gangjian Zhao, Zhe Zhang, Kaipeng Jia, Zesheng An, Houyuan Chen, Shizheng Guo, Yiduo Bai
Journal: Journal of Clinical Oncology (2023)

e16596 Background: Pts with multiple or tumors with large invasion areas that are incompletely resectable through TURBT would be recommended for radical cystectomy in the clinical treatment. The KEYNOTE-057 and SWOG S1605 studies have illuminated the efficacy of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). This trial was designed to evaluate the efficacy and safety of tislelizumab (ICI) plus nab-paclitaxel (MTI) in HR-NMIBC pts. Methods: TRUCE-02 is a single-arm phase II study testing systemic tislelizumab 200mg on days 1 plus nab-paclitaxel 200mg on days 2 every 3 weeks (Q3W) for one year for NMIBC pts with incompletely resectable tumor by TURBT. Here we report the results for all eligible patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate when pts received 3 or 4 cycles of therapy. Duration of complete response (DOR), cystectomy-free survival (CFS), overall survival (OS), and progression-free survival (PFS) using Kaplan-Meier methods (KM) were secondary endpoints. Results: Between July 2020 and December 2022, 69 pts were enrolled and included in the safety analysis, and, of those, 56 pts were eligible and included in the efficacy analysis. 34 (60.7%; 95% CI 46.8%, 73.2%) out of 56 pts achieved CR condition when completing 3 or 4 treatment cycles. At 12 months, the estimated DOR after CR was 88.1% (95% CI 76.2%, 99.9%); the median DOR was not reached. At 18 months, the estimated CFS was 70.0% (95% CI 58.1%, 84.3%), OS was 90.6% (95% CI 82.9%, 99.0%), and PFS was 74.4% (95% CI 62.5%,80.0%); the median CFS, OS, and PRS were not reached. 65 (94%) of 69 pts had treatment-related adverse events (trAEs). The most common trAEs were alopecia 47(68%), fatigue 44(64%), and rash 25(36%). 8 grade 3-4 trAEs occurred in 6 (9%) pts, including adrenal insufficiency in 2 (3%), rash in 1 (1%), myalgia or arthralgia in 1 (1%), increased creatine kinase isoenzyme in 1 (1%), hepatic enzymes increase in 1 (1%), increased glutamyl transpeptidase in 1 (1%), and decreased white blood cell count in 1 (1%). No trAE-related death was reported. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a durable and clinically meaningful activity in treating HR-NMIBC. The safety profile was consistent with that of previous experience and no new safety concerns. Clinical trial information: NCT04730232 .
Role of cytoreductive nephrectomy (CN) in metastatic clear cell renal cell carcinoma (mccRCC) in the era of immunotherapy (IO): An analysis of the National Cancer Database (NCDB).
Authors: Maroun Bou Zerdan, Roger Wong, Hanan Goldberg, Alina Basnet
Journal: Journal of Clinical Oncology (2023)

4552 Background: The role of CN remains questionable after the well intentioned two large prospective trials, SURTIME AND CARMENA, failed to show the benefit of CN for mccRCC, with Sunitinib as standard of care. Methods: We identified stage IV mccRCC only patients (pts) who received IO with or without surgery in the NCDB 2004-2018. Overall survival (OS) was calculated among three groups of IO alone (group (gr)1), IO followed by CN (gr2), CN followed by IO (gr3). Cox models compared OS by treatment group after adjusting for sociodemographic, health, and facility variables. Results: From 615,519 renal cancer cases, 2,903 met our criteria. 6.96% of ccRCC had sarcomatoid histology. Pts in the gr 2 and gr 3 had 63%, 95% CI [0.265-0.510] and 46%, 95% CI [0.487- 0.594], P= 0.001, risk reduction in mortality compared to IO alone. Black race compared to white race, education attainment quartile &lt; 6.3% compared to &gt; 17.6%, uninsured pts compared to privately insured, and pts treated at community cancer center compared to academic center had an increased mortality risk by 16%, 95% CI [0.980-1.387] (P= 0.083), 26%, 95% CI [1.054-1.511] (P= 0.011), 30%, 95% CI [1.003-1.683] (P= 0.047), 44%, 95% CI [1.161-1.779] (P= 0.001) respectively. Median income quartiles ranging &gt; 63k, had 25% reduction in mortality over income quartiles &lt; 40k, 95% CI [0.630-0.902] (P= 0.002). Regardless of the sequence of CN, partial nephrectomy was minimally used. Pts with brain and liver metastasis had a 48% (P= 0.063) and a 79% (P= 0.001) chance of increased risk of mortality. Conclusions: Pts receiving CN regardless of sequence with IO did better than IO alone in this national registry-based adjusted analysis for mccRCC. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification of pts was not done however Charlson-Deyo Comorbidity Index, visceral/brain metastasis were accounted for in OS analysis. Limitations inherited in the retrospective nature of this study are lack of randomization and pts’ and physicians’ choice. We believe the role of CN does warrant prospective validation in the era of IO for stage IV ccRCC. OS at 2 and 5 yrs for all three groups, with respective 95% CI. [Table: see text]
Updated results of the phase 1 I-FLOAT trial: Safety and efficacy of combining genotype-guided irinotecan with 5FU, leucovorin, oxaliplatin and docetaxel (gFOLFOXIRITAX) in advanced upper GI cancers.
Authors: Koosha Paydary, Colton Loew, Aurelie Desgardin, Ardaman Shergill, Natalie Marie Reizine, Chanelle Robinzine, Christine Racette, Elena Ignatiev, Anu Radha Neerukonda, Yuan Ji, Blase N. Polite, Chih-Yi Liao
Journal: Journal of Clinical Oncology (2023)

e16038 Background: 5FU, Oxaliplatin (ox), irinotecan (iri) and docetaxel (tax) are each active in upper GI cancers; however, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms may predispose to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of therapy (tx) among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. We report the updated results of the I-FLOAT trial. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and H risk groups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu &amp; Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1) &amp; ctDNA response (&gt;50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-1/1/2023, 27 pts (11F, 16M) enrolled: median age 51 (range 21-76); 9 ECOG PS 1, UGT-L:I:H with 6:18:3 pts; 12 esophageal, 6 gastric, 8 pancreatic, and 1 bile duct cancer; 3 pts HER2+; 22 metastatic, 5 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.2-4.7) and 4.06 (1.89-27.6), respectively; 81% (22/27) of pts had a NLR &gt; 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 5 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax), one G3 fatigue (UGT-I DL2/DL2 Iri/Tax) and one G3 diarrhea and neutropenic fever (UGT-L DL4/DL1 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, &amp; UGT-L DL4/DL1. The most frequent any Gr tx related toxicities: diarrhea (78%), fatigue (74%), nausea (70%), neuropathy (67%), anorexia (52%), elevated LFT (48%), anemia (37%), vomiting (37%). Of evaluable pts across all cohorts, PR/CR was seen in 18/22 (82%) patients, with 2 (9%) SD and 2 (9%) PD for a disease control rate of 91%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX continues to demonstrate tolerability at initial DLs of Iri/Tax. Efficacy is promising and could be an aggressive approach in upper GI cancers with high relapse risk in curative-intent settings. Clinical trial information: NCT04361708 .
Efficacy and safety of camrelizumab combined with apatinib in the treatment of advanced gastric cancer: Preliminary results from a multicenter, prospective study.
Authors: Yifu He, Bing Hu, Ke Liu, Xiaofei Cheng, Huaidong Cheng, Mo Chen, Changlu Hu, Chenghui Li, Xinkuan Mei, Jianfeng Liu, Hu Liu, Gang Wang, Hongxia Li, Dingqing Zhang, Huiqin Luo
Journal: Journal of Clinical Oncology (2023)

e16035 Background: There is an urgent need to find new therapeutic drugs/regimens for advanced gastric cancer. Camrelizumab combined with apatinib and chemotherapy has shown a high objective response rate and survival benefit in the first- and second-line treatment of advanced gastric cancer. Therefore, we conducted a prospective, observational study to analyze the efficacy and safety of camrelizumab combined with apatinib and chemotherapy in the first- and second-line treatment of advanced gastric cancer. Methods: This was a multicenter, observational study enrolling patients aged ≥ 18 years with an ECOG PS of 0-2 and pathologically or histologically confirmed advanced gastric cancer. Results: By January 9, 2023, 207 patients with advanced gastric cancer from 32 centers were enrolled. Most patients were male (138 [66.7%]), stage IV (151 [72.9%]), and ECOG PS of 1 (145 [70.0%]) with a median age of 66 years. The degree of differentiation was mainly moderate and low (155 [74.9%]). 109 patients (52.7%) had a surgical history of the primary lesion, 123 (59.4%) had previously received chemotherapy, and 115 (55.6%) had received COVID-19 vaccine. The first-line treatment included camrelizumab plus chemotherapy for 4-6 cycles followed by apatinib in 68 patients (32.9%), and camrelizumab plus chemotherapy and apatinib in 51 (24.6%). Second-line treatment included camrelizumab plus apatinib for 35 patients (16.9%), chemotherapy and apatinib for 44 (21.3%), and other treatments for 9 (4.3%). Clinical efficacy was evaluated in 52 patients. There were 20 patients with partial response, 26 with stable disease, and 6 with progressive disease. The overall objective response rate (ORR) was 38.46% and disease control rate (DCR) was 88.46%. The ORR and DCR in the first-line setting were 50.00% and 100.00%, and ORR and DCR in the second-line setting were 16.67% and 66.67%. Furthermore, the ORR was 40.63% and the DCR was 90.63% in patients vaccinated against COVID-19 compared to 40.00% and 85% in unvaccinated patients. The median PFS and OS have not been reached. The incidence of adverse events (AEs) was 80.4% and the incidence of grade≥3 AEs was 3.5%. The most common AEs were reactive cutaneous capillary endothelial proliferation (71.3%), nausea (51.0%), leukocyte reduction (38.46%), and hypertension (13.3%). Conclusions: In this real-world study of gastric cancer, the first-line treatment showed good efficacy, suggesting early administration with combination treatment may bring more benefits to the patients. Additionally, COVID-19 vaccination did not affect the efficacy of combination treatment. Further validation of these preliminary results is warranted. Clinical trial information: ChiCTR2200059650 .
Treatment patterns post atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: Real-world analysis at Veterans Health Administration comparing lenvatinib vs. sorafenib.
Authors: Tamarah Aldawoodi, Munaf Alkadimi, Kana Lucero, Lauren Diaz Boyle, Maria Elena Fierro, Michael Mader, Kathleen Franklin, Zohra Nooruddin
Journal: Journal of Clinical Oncology (2023)

e16195 Background: Atezolizumab plus Bevacizumab (A+B) has been the standard first-line therapy for advanced hepatocellular carcinoma (HCC) patients. There needs to be more data on the efficacy and selection of optimal sequences following resistance to A+B. Our study aims to review treatment patterns for disease progression following A+B, focusing on the most common 2nd line treatment utilized by the Veterans Health Administration (VHA). Methods: Patients with advanced HCC receiving line A+B at the VHA between Dec 1, 2019, to Mar 1, 2022, were selected electronically using ICD-9 and ICD-10 codes. Abstractors reviewed EMR following each patient from their index date of A+B initiation, sequential therapies, until death, or their last VHA visit, with the study period ending on Jan 31, 2023. Results: Three hundred thirty-two patients received A+B during our study period, and 1/3rd (n = 107) of these patients went on second-line treatments. 87 % started Tyrosine Kinase Inhibitors with 52, 29,12, and 1 on Lenvatinib, Sorafenib, Cabozantinib, and Regorafenib, respectively. Two second-line cohorts were selected, A (52 on Lenvatinib) and B (29 on sorafenib). The median age was 66 yrs vs. 65 yrs in cohorts A and B, respectively. In both cohorts, 60% non-Hispanic White and 90% with ECOG ≤1, there were no statistically significant differences between both cohorts in overall and progression-free survival. The outcomes are shown. Conclusions: Despite minimal improvement in PFS and a lower discontinuation rate due to toxicity favoring Lenvatinib over Sorafenib, Sorafenib had slightly better overall survival. This study is one of the most significant projects that describes 2nd line treatment patterns post-A+B failure. Further studies are warranted to evaluate larger cohorts to study treatment sequencing in the second and third lines.[Table: see text]
Neoadjuvant nivolumab alone or in combination with relatlimab or ipilimumab in resectable head and neck squamous cell carcinoma (HNSCC).
Authors: Robert L. Ferris, William E. Gooding, Simion I. Chiosea, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Moon Jung Fenton, Heath Devin Skinner, Zahra Rahman Kelly, Housaiyin Li, Lazar Vujanovic, Dan Paul Zandberg
Journal: Journal of Clinical Oncology (2023)

6018 Background: PD-1 inhibition using nivolumab (nivo) monotherapy is modestly effective in metastatic HNSCC. Neoadjuvant trials using nivo may permit development of more effective combinations in surgically resectable HNSCC. We evaluated combinations with nivo plus additional immune checkpoints, CTLA-4 (ipilimumab, ipi) and LAG-3 (relatlimab, rela). Methods: Phase II randomized trial of neoadjuvant nivo alone (240 mg q2 weeks), or with ipi (1 mg/kg q3 weeks) or rela (160 mg q4 weeks) for 4 weeks prior to surgery. Response was scored using RECIST and standard pathologic response criteria. Patients were stratified by p16, PD-L1, and LAG-3, with staining assessed by immunohistochemistry. Freshly digested tumors were subjected to single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways to identify biomarkers of response or progression. The Cochran-Armitage trend test was used to explore associations with increasing pathological response efficacy. Results: 41 patients (pts) have been enrolled, with 33 evaluable for this analysis. Of these 33, median age is 63 (32-81), primary site oral cavity (n=25), oropharynx (n=5, 3 HPV), larynx (n=3), clinical T2 (n = 5), T3 (n = 12), T4 (n = 13), and cN0/1 (n = 22), cN2 (n = 9), and PD-L1 CPS &gt; 1 (n=25). There were no serious study drug-related AEs or unexpected surgical delays/complications. Pathologic response (Table) was more frequent with nivo/rela (11/13) vs. nivo/ipi (6/10) or nivo (4/10). Partial (&gt;50%) or major (&gt;90%) pathologic responses were more frequent and deeper in the combination arms. Minor (&lt;50%) pathologic responses were more frequent with nivo/rela, and similar between nivo/ipi and nivo. There was no association between RECIST response, PD-L1, or LAG3 and pathologic response. Combined PD-L1 and LAG3 expression was not associated with pathologic response in the nivo/rela arm, however more patients with combined positivity had a &gt;50% response (4 vs. 0). Expansion of CD8 + T cells, as well as expanded proportion of CD8 + CXCL13 + T cells in responder tumors were identified in post-treatment specimens using scRNAseq. Conclusions: Neoadjuvant nivo/ipi or nivo/rela combinations were safe and associated with promising pathologic responses compared to nivo monotherapy. Anti-tumor CD8 + T cell populations and targetable pathways are emerging in responder patients. The trial continues to enroll and further evaluation of this strategy is warranted. Clinical trial information: NCT04080804 . [Table: see text]